Zurich Center for Integrative Human Physiology

Zürich, Switzerland

Zurich Center for Integrative Human Physiology

Zürich, Switzerland

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Blau N.,University of Zürich | Blau N.,Zurich Center for Integrative Human Physiology | Van Spronsen F.J.,University of Groningen | Levy H.L.,Harvard University
The Lancet | Year: 2010

Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20 of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom. Possible future treatments include enzyme substitution with phenylalanine ammonia lyase, which degrades phenylalanine, and gene therapy to restore phenylalanine hydroxylase activity. © 2010 Elsevier Ltd.


Heintz C.,University of Zürich | Cotton R.G.H.,Human Variome Project | Blau N.,University of Zürich | Blau N.,Zurich Center for Integrative Human Physiology | Blau N.,University of Heidelberg
Human Mutation | Year: 2013

In about 20%-30% of phenylketonuria (PKU) patients (all phenotypes of PAH deficiency), Phe levels may be controlled through phenylalanine hydroxylase cofactor tetrahydrobiopterin therapy. These patients can be diagnosed by an oral tetrahydrobiopterin challenge and are characterized by mutations coding for proteins with substantial residual PAH activity. They can be treated with a commercially available synthetic form of tetrahydrobiopterin, either as a monotherapy or as adjunct to the diet. This review article summarizes molecular and metabolic bases of PKU and the importance of the tetrahydrobiopterin loading test used for PKU patients. On the basis of in vitro residual PAH activity, more than 1,200 genotypes from patients challenged with tetrahydrobiopterin were categorized as predictive for tetrahydrobiopterin responsiveness or non-responsiveness and correlated with the loading test, phenotype, and residual in vitro PAH activity. The coexpression of two distinct PAH mutant alleles revealed possible dominance effects (positive or negative) by one of the mutations on residual activity as result of interallelic complementation. The treatment of the transfected cells with tetrahydrobiopterin showed an increase in residual PAH activity with several mutations coexpressed. Tetrahydrobiopterin (BH4; Kuvan®) induces a gain-of-function in phenylalanine hydroxylase (PAH) in a multifactorialresponse mechanism with a notable stabilization of protein structure. In about 20%-30% of phenylketonuria patients (all phenotypes of PAH deficiency), Phelevels may be controlled through PAHcofactor BH4 therapy. A substantial residual PAH activity is essential for the stabilization of enzyme activity and depends on specific PAH gene variations and on interallelic complementation, as shown from in vitro co-expression experiments.© 2013 WILEY PERIODICALS, INC.


Blau N.,University of Heidelberg | Blau N.,University of Zürich | Blau N.,Zurich Center for Integrative Human Physiology
Expert Opinion on Drug Metabolism and Toxicology | Year: 2013

Introduction: Phenylketonuria (PKU) is caused by mutation of the enzyme, phenylalanine (Phe) hydroxylase (PAH). The hyperphenylalaninemia characteristic of PKU causes devastating neurological damage if not identified and treated at birth with a Phe-restricted diet. Sapropterin dihydrochloride, a pharmaceutical formulation of the natural cofactor for PAH (6R-tetrahydrobiopterin; BH4), is now available for the management of hyperphenylalaninemia in some PKU patients, including BH4 deficiencies. Sapropterin dihydrochloride improves dietary Phe tolerance in about 20% of patients with PKU. Areas covered: This evaluation describes the identification of patients suitable for treatment of sapropterin dihydrochloride, together with its indications, therapeutic properties and efficacy. Furthermore, the article reviews its safety and tolerability in patients with PKU or BH4 deficiency. Expert opinion: A reduction in blood Phe of at least 30% occurred in ∼ 20-30% of sapropterin-treated PKU patients (mostly with milder forms of PKU). Treatment with sapropterin resulted in clinically significant and sustained reductions in blood Phe concentrations and increased dietary Phe tolerance in well-designed clinical studies in PKU patients who responded to BH4. Successful treatment with sapropterin may lead to a relaxation of the Phe-restricted diet, although continued monitoring of blood Phe is required. Sapropterin was well tolerated. © 2013 Informa UK, Ltd.


Berger W.,University of Zürich | Berger W.,Neuroscience Center Zurich | Berger W.,Zurich Center for Integrative Human Physiology | Kloeckener-Gruissem B.,University of Zürich | And 2 more authors.
Progress in Retinal and Eye Research | Year: 2010

During the last two to three decades, a large body of work has revealed the molecular basis of many human disorders, including retinal and vitreoretinal degenerations and dysfunctions. Although belonging to the group of orphan diseases, they affect probably more than two million people worldwide. Most excitingly, treatment of a particular form of congenital retinal degeneration is now possible. A major advantage for treatment is the unique structure and accessibility of the eye and its different components, including the vitreous and retina. Knowledge of the many different eye diseases affecting retinal structure and function (night and colour blindness, retinitis pigmentosa, cone and cone rod dystrophies, photoreceptor dysfunctions, as well as vitreoretinal traits) is critical for future therapeutic development. We have attempted to present a comprehensive picture of these disorders, including biological, clinical, genetic and molecular information. The structural organization of the review leads the reader through non-syndromic and syndromic forms of (i) rod dominated diseases, (ii) cone dominated diseases, (iii) generalized retinal degenerations and (iv) vitreoretinal disorders, caused by mutations in more than 165 genes. Clinical variability and genetic heterogeneity have an important impact on genetic testing and counselling of affected families. As phenotypes do not always correlate with the respective genotypes, it is of utmost importance that clinicians, geneticists, counsellors, diagnostic laboratories and basic researchers understand the relationships between phenotypic manifestations and specific genes, as well as mutations and pathophysiologic mechanisms. We discuss future perspectives. © 2010 Elsevier Ltd.


O'Gorman R.L.,University of Zürich | Michels L.,University of Zürich | Edden R.A.,Johns Hopkins University | Murdoch J.B.,Toshiba Corporation | And 2 more authors.
Journal of Magnetic Resonance Imaging | Year: 2011

Purpose: To evaluate the reproducibility of γ-amino-butyric acid (GABA) and glutamate concentrations derived using three different spectral fitting methods, and to investigate gender-related differences in neurotransmitter levels. Materials and Methods: Single voxel MEGA-edited PRESS MR spectra were acquired from a 30-mL voxel in the dorso-lateral prefrontal cortex in 14 adult volunteers (7 female) at 3 Tesla (3T). For each participant, four consecutive resting spectra were acquired within the same scanning session. Metabolite concentrations were derived using LCModel, jMRUI, and locally written peak fitting software. The within-session reproducibility for each analysis method was calculated as the average coefficient of variation (CV) of the GABA and Glx (glutamate+glutamine) concentrations. Gender differences in GABA and Glx were evaluated using a two-tailed unpaired t-test. Results: LCModel provided the best reproducibility for both GABA (CV 7%) and Glx (CV 6%). GABA, Glx, and glutamate concentrations were significantly higher in the male participants, (P = 0.02, P = 0.001, and P < 0.001, respectively). Conclusion: GABA and glutamate can be quantified in vivo with high reproducibility (CV 6-7%) using frequency-domain spectral fitting methods like LCModel. However, the GABA and glutamate concentrations vary significantly between men and women, emphasizing the importance of gender-matching for studies investigating differences in neurotransmitter concentrations between mixed-cohort groups. Copyright © 2011 Wiley-Liss, Inc.


Moes A.D.,Erasmus Medical Center | Van Der Lubbe N.,Erasmus Medical Center | Zietse R.,Erasmus Medical Center | Loffing J.,University of Zürich | And 2 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2014

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions. © 2013 Springer-Verlag Berlin Heidelberg.


Werner E.R.,Innsbruck Medical University | Blau N.,University of Zürich | Blau N.,Zurich Center for Integrative Human Physiology | Blau N.,Research Center for Children | And 3 more authors.
Biochemical Journal | Year: 2011

BH 4 (6R-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, including four aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and three NOS (NO synthase) isoenzymes. Consequently, BH 4 is present in probably every cell or tissue of higher organisms and plays a key role in a number of biological processes and pathological states associated with monoamine neurotransmitter formation, cardiovascular and endothelial dysfunction, the immune response and pain sensitivity. BH 4 is formed de novo from GTP via a sequence of three enzymatic steps carried out by GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. An alternative or salvage pathway involves dihydrofolate reductase and may play an essential role in peripheral tissues. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase, except for NOSs, in which the BH 4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I. BH 4 biosynthesis is controlled in mammals by hormones and cytokines. BH 4 deficiency due to autosomal recessive mutations in all enzymes, except for sepiapterin reductase, has been described as a cause of hyperphenylalaninaemia. A major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others, appears to be an effect of oxidized BH 4, which leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS. Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability, and oral cofactor replacement therapy to stabilizemutant phenylalanine hydroxylase in the BH 4-responsive type of hyperphenylalaninaemia has an advantageous effect on pathological phenylalanine levels in patients. ©The Authors Journal compilation © 2011 Biochemical Society.


Jacobs R.A.,Zurich Center for Integrative Human Physiology | Jacobs R.A.,University of Zürich | Lundby C.,Zurich Center for Integrative Human Physiology | Lundby C.,University of Zürich
Journal of Applied Physiology | Year: 2013

Changes in skeletal muscle respiratory capacity parallel that of aerobic fitness. It is unknown whether mitochondrial content, alone, can fully account for these differences in skeletal muscle respiratory capacity. The aim of the present study was to examine quantitative and qualitative mitochondrial characteristics across four different groups (n = 6 each), separated by cardiorespiratory fitness. Highresolution respirometry was performed on muscle samples to compare respiratory capacity and efficiency in active, well-trained, highly trained, and elite individuals. Maximal exercise capacity (ml O2·min-1·kg-1) differed across all groups, with mean ± SD values of 51 ± 4, 64 ± 5, 71 ± 2, and 77 ± 3, respectively. Mitochondrial content assessed by citrate synthase activity was higher in elite trained compared with active and well-trained (29 ± 7 vs. 16 ± 4 and 19 ± 4 nmol·min -1·mg wet wt-1, respectively). When normalizing respiration to mitochondrial content, the respiratory capacities during maximal fatty acid oxidation (P = 0.003), maximal state 3 respiration (P = 0.021), and total electron transport system capacity (P = 0.008) improved with respect to maximal exercise capacity. The coupling efficiency of β-oxidation, however, expressed no difference across groups. These data demonstrate the quantitative and qualitative differences that exist in skeletal muscle mitochondrial respiratory capacity and efficiency across individuals that differ in aerobic capacity. Mitochondrial-specific respiration capacities during β-oxidation, maximal oxidative phosphorylation, and electron transport system capacity all correspondingly improve with aerobic capacity, independent of mitochondrial content in human skeletal muscle. Copyright © 2013 the American Physiological Society.


Brugger P.,University of Zürich | Brugger P.,Zurich Center for Integrative Human Physiology | Lenggenhager B.,University of Zürich | Lenggenhager B.,Zurich Center for Integrative Human Physiology
Current Opinion in Neurology | Year: 2014

Purpose of review The experience of ourselves as an embodied agent with a first-person perspective is referred to as 'bodily self'. We present a selective overview of relevant clinical and experimental studies. Recent findings Sharing multisensory body space with others can be observed in patients with structurally altered bodies (amputations, congenital absence of limbs), with altered functionality after hemiplegia, such as denial of limb ownership (somatoparaphrenia) and with alterations in bodily self-consciousness on the level of the entire body (e.g. in autoscopic phenomena). In healthy participants, the mechanisms underpinning body ownership and observer perspective are empirically investigated by multisensory stimulation paradigms to alter the bodily self. The resulting illusions have promoted the understanding of complex disturbances of the bodily self, such as out-of-body experiences. We discuss the role of interoception in differentiating between self and others and review current advances in the study of body integrity identity disorder, a condition shaped as much by neurological as by social-psychological factors. Summary We advocate a social neuroscience approach to the bodily self that takes into account the interactions between body, mind and society and might help close the divide between neurology and psychiatry. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Jacobs R.A.,Zurich Center for Integrative Human Physiology | Jacobs R.A.,University of Zürich | Meinild A.-K.,University of Zürich | Nordsborg N.B.,Copenhagen University | And 2 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013

Lactate is an important intermediate metabolite in human bioenergetics and is oxidized in many different tissues including the heart, brain, kidney, adipose tissue, liver, and skeletal muscle. The mechanism(s) explaining the metabolism of lactate in these tissues, however, remains unclear. Here, we analyze the ability of skeletal muscle to respire lactate by using an in situ mitochondrial preparation that leaves the native tubular reticulum and subcellular interactions of the organelle unaltered. Skeletal muscle biopsies were obtained from vastus lateralis muscle in 16 human subjects. Samples were chemically permeabilized with saponin, which selectively perforates the sarcolemma and facilitates the loss of cytosolic content without altering mitochondrial membranes, structure, and subcellular interactions. High-resolution respirometry was performed on permeabilized muscle biopsy preparations. By use of four separate and specific substrate titration protocols, the respirometric analysis revealed that mitochondria were capable of oxidizing lactate in the absence of exogenous LDH. The titration of lactate and NAD+ into the respiration medium stimulated respiration (P ≤ 0.003). The addition of exogenous LDH failed to increase lactate-stimulated respiration (P = 1.0). The results further demonstrate that human skeletal muscle mitochondria cannot directly oxidize lactate within the mitochondrial matrix. Alternately, these data support previous claims that lactate is converted to pyruvate within the mitochondrial intermembrane space with the pyruvate subsequently taken into the mitochondrial matrix where it enters the TCA cycle and is ultimately oxidized. © 2013 the American Physiological Society.

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